Oral medicaments are usually in the form of tablets, pills or capsules, despite the fact that many people, especially children, the elderly and certain dysphagics, have difficulty swallowing them. It is probable that most people would prefer to take medicines in the form of a pleasant tasting liquid, if they were available in such a form. Parenteral medicaments, including intravenous, intramuscular and intraperitoneal preparations must normally be administered in liquid form, which causes serious problems, restricting the use of many products. A variety of inhaled preparations are also administered in liquid form, using a range of nebulisers and pressurised devices.
The main reason why more medicines are not available in liquid form is that the majority are insoluble, or only sparingly soluble, in water or any other acceptable solvent. To be administered as liquids they would have to be suspended. However medicinal suspensions undergo sedimentation on standing, leading to a risk of under or overdosing, if instructions to shake the bottle thoroughly are not fully complied with.
A further problem is that only relatively low concentrations of solids can be suspended, without the product becoming unacceptably viscous. For these reasons the use of oral suspensions has largely been confined to paediatric medicine, where only a fraction of the adult dose may be required. Thus for example suspensions of paracetamol are widely used for treating infants, but no adult equivalent is available. Also, for similar reasons, many parenteral preparations have to be administered in larger than desired volumes over longer than desirable time frames, to achieve the necessary therapeutic dosing range of the drug.
Attempts to solve the problem of dispersing pharmaceuticals in water have hitherto usually involved the use of thickeners (e.g. gums or polymers) to raise the viscosity of the liquid medium. Thickeners only retard sedimentation. They do not provide stable suspensions. Thus, for example, paediatric suspensions of paracetamol, although very viscous, are not stable.
The only alternative to the use of viscosifiers for suspending pharmaceuticals has been to make colloidal dispersions. The latter contain particles of about 1 micron or smaller, which are prevented from sedimenting by Brownian motion. Such systems are incapable of dispersing relatively coarse particles. Since colloidal particles tend to increase in size with time by Ostwald ripening and/or agglomeration, colloidal suspensions are liable to undergo sedimentation.
In contrast to the foregoing, structured suspending systems depend on the rheological properties of the suspending medium to immobilise the particles, irrespective of size. This requires the suspending medium to exhibit a yield point, which is higher than the sedimenting or creaming force exerted by the suspended particles, but low enough to enable the medium to flow under externally imposed stresses, such as pouring and stirring, like a normal liquid. The structure reforms sufficiently rapidly to prevent sedimentation, once the agitation caused by the external stress has ceased. The only structured systems, sufficiently effective to have found widespread application, have been based on aqueous surfactant mesophases.
The terms “structured system”, “structured surfactant system”, “structured suspending system” as used interchangeably herein mean a composition comprising water, surfactant and any structurants required to impart suspending properties to the surfactant. These components together form a mesophase, or a dispersion of a mesophase in a continuous aqueous medium, which has the ability to suspend non-colloidal, water-insoluble particles, while the system is at rest, without sedimentation.
Structured surfactants generally comprise an Lα-phase, in which bilayers of surfactant are disposed with the hydrophobic “tail groups” of the surfactant on the inside and the hydrophilic “head groups” on the outside of the bilayer. The bilayers lie in a parallel or concentric arrangement, usually alternating with layers of an aqueous medium.
Lα-phases are sometimes referred to in the art as G-phases. They are commonly characterised by the textures observed under the polarising microscope and/or by small angle X-ray diffraction, which usually shows peaks indicative of lamellar symmetry, e.g. first, second and sometimes higher order peaks with a d-spacing in a simple integral ratio 1:2:3. The d-spacing is given by the formula 2π/Q, where Q is the momentum transfer vector.
Structured suspending systems typically comprise dispersed lamellar, spherulitic and/or expanded lamellar phases. Dispersed lamellar phases are two phase systems, in which domains of a lamellar phase are dispersed in, or interspersed with, an aqueous phase to form a gel. They are described in EP 0 086 614.
Spherulitic phases comprise spheroidal bodies, usually referred to in the art as spherulites, with an onion-like structure comprising concentric shells of surfactant. The spherulites usually have a diameter in the range 0.1 to 15 microns and are dispersed in an aqueous phase in the manner of a classical emulsion, but interacting to form a structured system. Spherulitic systems are described in more detail in EP 0 151 884.
The third type of structured system is the expanded Lα-phase, which is a single phase having a wider d-spacing than conventional Lα-phase. Conventional Lα-phases, contain 60 to 75% by weight surfactant and have a d-spacing of 4 to 7 nanometers. Attempts to suspend solids in such phases result in stiff pastes which are either non-pourable, unstable or both. Expanded Lα-phases have a d-spacing greater than 8, e.g. 10 to 100 nanometers. They may be prepared by adding electrolyte to aqueous surfactants at concentrations below those required to form a normal Lα-phase. Expanded Lα-phases are described in more detail in EP 0 530 708.
Most structured surfactants require the presence of a structurant, as well as surfactant and water in order to form systems capable of suspending solids. The term “structurant” is used herein to describe any non-surfactant capable, when dissolved in water, of interacting with surfactant to form or enhance (e.g. increase the yield point of) a structured system. It is typically a surfactant-desolubiliser, e.g. an electrolyte. However, certain relatively hydrophobic surfactants such as isopropylamine alkyl benzene sulphonate are self-structuring, and can suspend solids in the absence of any structurant. Self structuring systems are described in EP 0 414 549.
WO 01/00788 describes the use of carbohydrates such as sugars and alginates as deflocculants in structured surfactant compositions. The latter comprise surfactant, water and electrolyte in proportions adapted to form flocculated two-phase structured surfactant systems in the absence of the carbohydrate.
The use of deflocculant polymers to prepare clear spherulitic or other dispersed Lα structured systems, by shrinking the spherulites or other Lα domains to a size below the wave length of visible light, has been described in WO 00/63079. The latter also describes the use of sugar to modify the refractive index of the aqueous phase as an alternative means of obtaining clear liquids.
It is known from WO 01/05932 that carbohydrates can interact with surfactants to form suspending structures. Such systems generally exhibit even greater d-spacings than the electrolyte-structured expanded Lα-phases, described in EP 0 530 708. The d-spacings of the sugar-structured systems, described in WO 01/05932, are typically greater than 15 nm, and may, for example, be as high as 50 nm. Such systems are generally clear or translucent.
In addition to their use to suspend dispersed particles, structured systems may be used in solid-free liquid formulations, as taught in U.S. Pat. No. 4,244,840, e.g. to modify the rheology and/or appearance of the composition.
Several of the above publications have suggested the use of structured surfactants to suspend pharmaceutical ingredients for topical application. However none of the structured systems described hitherto has proved acceptable to the pharmaceutical industry for medicines for internal use.
The only structured systems to have found practical application have been in laundry detergents, hard surface cleaners and personal care formulations such as shampoos. These rely to a substantial extent on anionic surfactants, and especially sulphonates and sulphates, which readily form suspending structures, but which are not acceptable for oral administration.
The surfactants approved for pharmaceutical and food use are almost exclusively non-ionic and do not readily form structured systems. One problem with non-ionic surfactants is high temperature instability of the lamellar mesophases.
WO2005007133 referred to the use of non-ionic structured systems to suspend various active ingredients, including pharmaceuticals and described a paracetamol suspension, which could contain up to 20% paracetamol. However the formulation required the presence of 15% by weight of surfactant, which is undesirably high for a product intended for internal use, particularly as the surfactant system contains high levels of ethoxylate. The composition has an unpleasant bitter taste and is somewhat physically aggressive to biological systems. Like most conventional suspensions with high loading of active material, the formulation is too viscous for convenient dispensing.
The specification teaches that at least 30% of bent chain groups are essential for high temperature stability. The only compounds with bent chain groups, as defined in WO2005007133, that are accepted for pharmaceutical use are oleyl compounds, which can give rise to rancid odours and flavours on standing. High levels of oleate in products intended for oral ingestion generally require the inclusion of antioxidants. The definition of “bent chain” excludes polyunsaturated groups, such as linolenyl groups and other omega 3 groups which would be preferable to oleyl.
As a result of these problems, and despite the obvious deficiencies of the existing methods, structured systems have still not found an application in the pharmaceutical industry.